Incidence of catheter-related complications in patients with central venous or hemodialysis catheters: a health care claims database analysis.

BACKGROUND: Central venous catheter (CVC) and hemodialysis (HD) catheter usage are associated with complications that occur during catheter insertion, dwell period, and removal. This study aims to identify and describe the incidence rates of catheter-related complications in a large patient population in a United States-based health care claims database after CVC or HD catheter placement. METHODS: Patients in the i3 InVision DataMart® health care claims database with at least 1 CVC or HD catheter insertion claim were categorized into CVC or HD cohorts using diagnostic and procedural codes from the US Renal Data System, American College of Surgeons, and American Medical Association's Physician Performance Measures. Catheter-related complications were identified using published diagnostic and procedural codes. Incidence rates (IRs)/1000 catheter-days were calculated for complications including catheter-related bloodstream infections (CRBSIs), thrombosis, embolism, intracranial hemorrhage (ICH), major bleeding (MB), and mechanical catheter-related complications (MCRCs). RESULTS: Thirty percent of the CVC cohort and 54% of the HD cohort had catheter placements lasting <90 days. Catheter-related complications occurred most often during the first 90 days of catheter placement. IRs were highest for CRBSIs in both cohorts (4.0 [95% CI, 3.7-4.3] and 5.1 [95% CI, 4.7-5.6], respectively). Other IRs in CVC and HD cohorts, respectively, were thrombosis, 1.3 and 0.8; MCRCs, 0.6 and 0.7; embolism, 0.4 and 0.5; MB, 0.1 and 0.3; and ICH, 0.1 in both cohorts. Patients with cancer at baseline had significantly higher IRs for CRBSIs and thrombosis than non-cancer patients. CVC or HD catheter-related complications were most frequently seen in patients 16 years or younger. CONCLUSIONS: The risk of catheter-related complications is highest during the first 90 days of catheter placement in patients with CVCs and HD catheters and in younger patients (≤16 years of age) with HD catheters. Data provided in this study can be applied toward improving patient care.

Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study.

BACKGROUND: Patients with rheumatoid arthritis (RA) are known to be at increased risk of infection, particularly if they are taking drugs with immunomodulatory effects. There is a need for more information on the risk of influenza in patients with RA. METHODS: A retrospective cohort study was carried out using data gathered from a large US commercial health insurance database (Thomson Reuters Medstat MarketScan) from 1 January 2000 to 31 December 2007. Patients were ≥18 years of age, with at least two RA claims diagnoses. The database was scanned for incidence of seasonal influenza and its complications on or up to 30 days after an influenza diagnosis in RA patients and matched controls. Other factors accounted for included medical conditions, use of disease-modifying anti-rheumatic drugs (DMARDs), use of biological agents, influenza vaccination and high- or low-dose corticosteroids. Incidence rate ratios (IRRs) were calculated for influenza and its complications in patients with RA. RESULTS: 46,030 patients with RA and a matching number of controls had a median age of 57 years. The incidence of influenza was higher in RA patients than in controls (409.33 vs 306.12 cases per 100,000 patient-years), and there was a 2.75-fold increase in incidence of complications in RA. Presence or absence of DMARDs or biologics had no significant effect. The adjusted IRR of influenza was statistically significant in patients aged 60-69 years, and especially among men. A significantly increased rate of influenza complications was observed in women and in both genders combined (but not in men only) when all age groups were combined. In general, the risk of influenza complications was similar in RA patients not receiving DMARDs or biologics to that in all RA patients. Pneumonia rates were significantly higher in women with RA. Rates of stroke/myocardial infarction (MI) were higher in men, although statistical significance was borderline. CONCLUSIONS: RA is associated with increased incidence of seasonal influenza and its complications. Gender- and age-specific subgroup data indicate that women generally have a greater rate of complications than men, but that men primarily have an increased rate of stroke and MI complications. Concomitant DMARD or biological use appears not to significantly affect the rate of influenza or its complications.

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.

Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): A nested case-control analysis.

OBJECTIVE: Giant cell arteritis (GCA) is an inflammatory vasculitis preferentially affecting large and medium-sized arteries. High-dose oral glucocorticoids (GCs) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink (CPRD), we examined the risk of oral GC-related serious adverse events (SAEs) in a UK population of patients with giant cell arteritis (GCA). METHODS: We conducted a series of nested case-control analyses in GCA patients to examine the effect of increasing dose of prednisolone on the risk of developing diabetes, glaucoma, osteoporosis, fractures, serious infection requiring hospitalization, and death. We used conditional logistic regression to calculate the unadjusted and multivariate odds ratios (ORs) with 95% CIs for the associations between prednisolone use and the risks of all outcomes of interest. We stratified the analyses by increasing cumulative prednisolone use and average daily dose. RESULTS: In the multivariate analyses, we observed a trend of increasing risk of diabetes and osteoporosis with increasing cumulative dose of oral prednisolone (ptrend < 0.05). GCA patients in the highest daily dose category (30mg/d) had an increased risk of diabetes (adjusted OR, 95% CI) (4.7, 2.8-7.8), osteoporosis (1.9, 1.2-2.9), fractures (2.6, 1.6-4.3), glaucoma (3.5, 2.0-6.1), serious infection (3.3, 2.2-5.2), and death (2.1, 1.3-3.5) compared to those with lower average daily prednisolone doses (5mg/d). CONCLUSION: Compared to lower average daily prednisolone doses, high average daily doses were associated with an increased risk of serious adverse effects.

Incidence of outcomes potentially associated with corticosteroid therapy in patients with giant cell arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is an inflammatory disorder of blood vessels that preferentially affects large- and medium-sized arteries. High-dose oral corticosteroids (CS) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink, we quantified and compared the incidence of selected potentially CS-associated adverse outcomes in patients with and without GCA. METHODS: We conducted a retrospective follow-up study of GCA and non-GCA patients to examine the incidence of adverse outcomes attributable to CS use. Eligibility criteria for the GCA group included a first-time diagnosis of GCA at age 50 years or older with receipt of ≥1 prescription(s) for prednisolone. GCA patients were matched to a GCA-free comparison group of equal size on age, sex, general practice, and calendar time. We estimated incidence rates and incidence rate ratios (IRRs) for diabetes, osteoporosis, glaucoma, fractures, serious infection requiring hospitalization, and death for GCA and non-GCA patients and compared all-cause hospitalizations between the two groups. RESULTS: The cohort consisted of 5011 GCA and 5011 matched non-GCA patients. Approximately 74% were women, and mean age at GCA diagnosis was 72.9 years. The IR for all outcomes was greater in the GCA group than the non-GCA group. IRRs [95% confidence intervals (CIs)] were as follows: diabetes 1.4 (1.2-1.7), osteoporosis 2.4 (2.1-2.8), fractures 1.4 (1.2-1.6), glaucoma 2.0 (1.6-2.5), serious infection requiring hospitalization 1.5 (1.3-1.7), and death 1.2 (1.0-1.3). CONCLUSION: Compared with age- and sex-matched non-GCA patients, patients with GCA were at increased risk for diabetes, osteoporosis, fracture, and glaucoma and at a marginally increased risk for death.

Corticosteroid-related adverse events in patients with giant cell arteritis: A claims-based analysis.

OBJECTIVE: Corticosteroids (CS) are standard treatment for giant cell arteritis (GCA), but concerns persist over toxicities associated with long-term use. In this retrospective study of medical claims data, we estimated risks for adverse events (AEs) in CS-treated GCA patients. METHODS: Cox regression analyses with CS use as a time-dependent variable were conducted on data from the 2003 to 2012 Truven Health Analytics MarketScan Database. Patients 50 years of age and older who had ≥2 claims of newly diagnosed GCA, ≥1 filled oral CS prescription, and no AEs before GCA diagnosis were included. The primary outcome was presence of a new CS-related AE. RESULTS: In total, 2497 patients were included. Their mean age was 71.0 years, and 71% were women. Follow-up was 9680 patient-years (PY). CS treatment continued for a mean (SD) of 1.196 (729.2) days; mean (SD) prescribed cumulative CS dose was 6983.3mg (6519.9). The overall AE rate was 0.43 events/PY; the most frequent AEs were cataract and bone disease. For each 1000-mg increase in CS exposure, the hazard ratio (HR) increased by 3% (HR = 1.03; 95% CI: 1.02-1.05; P < 0.001). Additionally, statistically significant individual associations between increased CS exposure and AE risk were observed for bone-related AEs (P < 0.001), cataract (P < 0.001), glaucoma (P = 0.005), pneumonia (P = 0.003), and diabetes mellitus (P < 0.001 in a subset of patients with no previous history of diabetes). CONCLUSION: CS exposure significantly increased risk for potentially serious AEs, emphasizing a need for new treatment options for GCA patients.

Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab.

OBJECTIVE: To analyse malignancy rates in patients with rheumatoid arthritis (RA) treated with tocilizumab. METHODS: Patients who received tocilizumab or placebo+methotrexate/disease-modifying antirheumatic drugs in the double-blind phases of 5-phase three trials or who received at least 1 dose of tocilizumab in the long-term extension studies were analysed up to the 2 May 2012 cut-off date. Malignancies were monitored throughout the studies, analysed and adjudicated as malignant by medical review. Risk was compared with that in the general population using standardised incidence ratios (SIRs) based on data from the Surveillance Epidemiology and End Results SEER (US general population) and GLOBOCAN (non-US general population) databases. RESULTS: In total, 4009 patients in the tocilizumab all-exposure population were included. Mean treatment duration was 4.0 years (mean 5.1 (range 0.0-6.8); total observation time was 16 120.1 patient-years (PY). The adjudicated malignancy rate (95% CI) was 1.26/100 PY (1.09 to 1.44) and remained constant over time. The SIR (95% CI) for all malignancies combined, excluding non-melanoma skin cancer, was 1.36 (1.01 to 1.80) for US and 1.81 (1.44 to 2.23) for non-US populations, driven primarily by higher rates in lung and bronchus (US/non-US) malignancies and prostate cancer and non-Hodgkin lymphoma (non-US), in contrast to those for the general populations; these higher rates are in line with those expected in patients with RA or in the geographic regions studied. CONCLUSIONS: Malignancy rates remained stable with long-term tocilizumab treatment, and malignancy types and rates were consistent with those expected in patients with RA.

Incidence of giant cell arteritis and characteristics of patients: data-driven analysis of comorbidities.

OBJECTIVE: To establish the incidence of giant cell arteritis (GCA), cumulative use of prednisolone, and comorbidities most associated with GCA. METHODS: The data source was the UK Clinical Practice Research Datalink. Selection criteria included ≥1 record of a diagnostic term for GCA between January 1, 2000 and December 31, 2011, age ≥50 years, and ≥1 prescription of oral or systemic corticosteroid. Controls were selected randomly (2:1), with year of birth, practice, and followup duration (<2 or ≥2 years) as matching variables. Analysis was data driven; all comorbidities were identified in a 2-year window, with relative risk (RR) calculated and rank ordered. RESULTS: A total of 4,671 patients fulfilled the definition of GCA (incidence, 1.0 per 10,000 person-years), with highest incidence (7.4 per 10,000 person-years) in women ages 70-79 years. Of the 4,671 patients, 4,655 (99.7%) were prescribed prednisolone. In the group with ≥2 years' followup (n = 3,074), the mean number of prednisolone prescriptions was 32.1, and the mean cumulative dose was 8,640 mg; 1,034 patients (33.4%) received a cumulative dose of ≥10,000 mg. Comorbidities strongly associated with GCA were polymyalgia rheumatica (RR 14.9, 95% confidence interval [95% CI] 11.9-18.7), visual disturbances (RR 4.6, 95% CI 2.7-7.8), facial pain (RR 3.3, 95% CI 2.1-5.3), osteoporosis (RR 2.9, 95% 2.3-3.7), hypokalemia (RR 2.5, 95% CI 1.6-3.9), and various infections such as oral/esophageal thrush (RR 3.7, 95% CI 2.2-6.0) and herpes zoster (RR 2.6, 95% CI 1.6-4.1). CONCLUSION: GCA is relatively uncommon; its incidence peaks at age 70-79 years in women. Overall, GCA patients in the UK are treated with high cumulative prednisolone doses. Many conditions are associated with GCA, including several related to corticosteroid use.

Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study.

INTRODUCTION: Interstitial lung disease (ILD) is a common extra-articular condition in rheumatoid arthritis (RA), but few studies have systematically investigated its incidence and risk factors in patients receiving anti-tumor necrosis factor-alpha (anti-TNFα) agents or alternate mechanisms of action (MOAs) (e.g., T-cell, B-cell, and interleukin-6 inhibitors). METHODS: RA patients at least 18 years old were selected from the MarketScan databases (2010-2012) if they had at least one prescription/administration of abatacept, rituximab, tocilizumab, or anti-TNF after having discontinued a different biologic agent and meeting enrollment criteria. Cox models estimated the risk of incident ILD and ILD-related hospitalization. Sensitivity analyses used an alternate ILD case definition. RESULTS: We identified 13,795 episodes of biologic exposure in 11,219 patients. Mean (standard deviation) follow-up was 0.7 (0.5) years. Patients receiving alternate MOA agents were more likely to have had recent exposure to steroids, prior exposure to a greater number of biologics, and history of ILD, anemia, chronic obstructive pulmonary disease, and other pulmonary conditions. When the sensitive definition was used, unadjusted ILD incidence rates (95% confidence interval, or CI) ranged from 4.0 (1.6-8.2, abatacept) to 12.2 (5.6-23.2, infliximab) per 1000 person-years. Being older (hazard ratio (HR) 3.5; 95% CI 2.1-6.0), being male (HR 3.1; 95% CI 1.2-8.4), and having another pulmonary condition (HR 4.8; 95% CI 1.7-13.7) were associated with increased ILD incidence in either sensitive and/or specific models. There were no significant differences by biologic class. Hospitalization rates (95% CI) when the sensitive definition was used ranged from 55.6 (6.7-200.7, tocilizumab) to 262.5 (71.5-672.2, infliximab). In Cox models, recent methotrexate exposure was associated with reduced ILD hospitalization (HR 0.16; 95% CI 0.06-0.46), whereas being male (HR 2.5; 95% CI 1.3-4.8) and having had a hospitalization for asthma (HR 3.4; 95% CI 1.2-9.8) or ILD/pneumonia (HR 2.3; 95% CI 1.1-4.7) in the 12 months prior to index were associated with increased hospitalization risk. CONCLUSIONS: There were no significant differences in the risk of ILD and its related complications between RA patients receiving anti-TNFα agents and those receiving alternate MOA agents. Further studies are needed that account for differences in baseline characteristics in order to fully evaluate the risk of ILD and its complications.

Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources.

OBJECTIVES: To evaluate the magnitude of serious adverse events (SAEs) observed in postmarketing reports of tocilizumab (TCZ) for rheumatoid arthritis (RA) in relation to SAEs observed in TCZ clinical trials and external epidemiology data. METHODS: A total of 64,000 patient-years (PY) of TCZ exposure was needed to determine, with 90% power, whether rates of SAEs of interest (eg, death, hepatic, gastrointestinal, and cardiovascular) were ≥50% higher (agreed with the Food and Drug Administration) than expected. Reporting rates were calculated for spontaneously reported SAEs, open-label or unblinded postmarketing clinical trials (phase 3b/4), and a Japanese postmarketing surveillance program in the global postmarketing safety database. Event rates were calculated for the registrational placebo-controlled trials and long-term extension data. External comparators for anti-tumor necrosis factor (aTNF)-treated RA patients were derived from a US-based health care insurance claims database or published literature. RESULTS: The global postmarketing safety database provided 65,099 PY of TCZ exposure; the aTNF external comparator population provided 53,360 PY. Spontaneous reporting rates per 100 PY (95% confidence interval) were 8.3 (8.1, 8.5) SAEs, 0.39 (0.34, 0.44) deaths, 0.06 (0.04, 0.08) serious hepatic events, 0.15 (0.12, 0.18) serious gastrointestinal events, 0.09 (0.07, 0.12) serious myocardial infarctions, 0.15 (0.12, 0.18) serious strokes, and 0.07 (0.05, 0.09) cardiac deaths in the global postmarketing safety database. These were of similar magnitude to corresponding rates from registrational clinical trials, the aTNF external comparator population, and published literature. CONCLUSIONS: SAE rates observed among postmarketing TCZ users were similar to those of various comparison populations. Predetermined design of studies to compare postmarketing AEs using multiple data sources is a useful strategy that can be applied to other medications.

A study of influenza and influenza-related complications among children in a large US health insurance plan database.

BACKGROUND: Influenza places a substantial burden on the affected individual and society. While there are data available on the overall occurrence of influenza in children, less information is available on the differential impact of influenza on healthcare for previously healthy children and those at high risk of developing influenza-related complications. OBJECTIVE: To compare the frequency of influenza-related complications in healthy and 'at-risk' children, and quantify the associated use of medical resources and costs. DESIGN: Data were obtained from a large US-based health insurance plan database. MAIN OUTCOME MEASURES AND RESULTS: A total of 23 188 health insurance claims with an influenza diagnosis were identified over the 3-year period 1995-1997 (3 247 834 patient-years). Influenza-related complications were observed in approximately a quarter of the total diagnosed cases, with younger children (0-4 years of age) at substantially greater risk. 'At-risk' children were more likely to develop influenza-related complications than otherwise healthy children. The greatest difference in incidence rate in the 0-4 year age group was for asthma (incidence rate ratio 8.7, 95% CI 5.2-14.4), and in the 5-14 year age group for asthma (incidence rate ratio 8.5, 95% CI 5.2-13.7) and acute sinusitis (incidence rate ratio 2.7, 95% CI 1.2-5.4). The average direct medical costs of influenza in children under 15 years with complications were more than 3.5 times higher than those without. CONCLUSIONS: Measures to prevent and treat influenza-related complications are certainly warranted for at-risk children, although the elevated incidence rates for several common complications even among healthy children should prompt consideration of these measures for all children.

Risk of mortality, fatal infection, and fatal malignancy related to use of anti-tumor necrosis factor-α biologics by rheumatoid arthritis patients.

OBJECTIVE: To estimate rates of all-cause mortality, fatal infection, and fatal malignancy in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor-α (anti-TNF) biologics. METHODS: A retrospective cohort study of RA patients initiating therapy with adalimumab, etanercept, or infliximab from January 2000 to December 2008 was conducted using an administrative database of a large health care insurer. Patients were followed for the occurrence of fatal events, which were identified using the National Death Index database. Overall and anti-TNF biologic-stratified incidence rates per 1000 person-years were calculated. Primary analyses were time-on-drug based on current anti-TNF biologic exposure on the outcome date for fatal infection and intent-to-treat based on the anti-TNF biologic initiated at cohort entry for fatal malignancy. RESULTS: Seven thousand seven hundred thirty-four patients initiated an anti-TNF biologic with 13,296 person-years of observation. Seventy-one deaths were identified, including 12 fatal infections and 21 fatal malignancies. The all-cause mortality rate was 5.34 per 1000 person-years. Incidence rates for fatal infection were similar among anti-TNF biologic current exposure groups (0.78 to 0.88 per 1000 person-years). Incidence rates for fatal malignancy were similar among anti-TNF biologic initiator groups (1.24 to 1.84 per 1000 person-years). CONCLUSIONS: The all-cause mortality rate in RA patients treated with anti-TNF biologics was lower than in previous studies in similar non-US populations, but comparable to mortality rates in the US general population. Fatal infection and fatal malignancy rates were similar across anti-TNF biologic groups. Further studies, designed to detect risk differences associated with anti-TNF biologic use and baseline risk factors, would provide additional information.

Risk of significant infection in rheumatoid arthritis patients switching anti-tumor necrosis factor-α drugs.

OBJECTIVES: To describe rates of first significant infection of rheumatoid arthritis patients who switch between anti-tumor necrosis factor (aTNF) drugs. METHODS: Subjects with rheumatoid arthritis who received only aTNF drugs were observed in an insurance claims database from January 2001 to December 2007. Nonswitchers (NS) remained on one aTNF throughout the study period (date of the first aTNF claim was the index date); switchers (S) received at least one other aTNF (claim date for the 2nd agent was the index date). Significant infections included those that required intravenous antibiotics or hospitalization. Two attributable risk periods were used: (1) an infection occurring ≤90 days following a claim for an aTNF (90-day) and (2) an infection occurring after the index date (ever-treated). Follow-up was censored at the first occurrence of a significant infection event, end of eligibility, or end of study period. Data were analyzed using Cox regression. RESULTS: In 13,752 NS and 2293 S patients, time-stratified rates declined 2- to 3-fold between the first year versus ≥2 years. Risk of significant infection was not different for either attribution model [90-day hazard ratio (HR) = 0.93, 95CI: 0.74 to 1.17, P = 0.55; ever treated HR = 0.94, 95CI: 0.78 to 1.15, P = 0.57]. First and second year rates were similar. Predictors included age ≥50 years; history of significant or opportunistic infection, diabetes, respiratory disease; Charlson score ≥2; or prior hospitalizations. CONCLUSIONS: The risk of a significant infection was not different between NS and S patients. Regardless of switching status, the rate of infection was greater in the first year. This study was limited by the lack of clinical data to determine the reason for switching.